Molecular Neurodegeneration最新文献

{"title":"Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease","authors":"Henna Martiskainen, Roosa-Maria Willman, Päivi Harju, Sami Heikkinen, Mette Heiskanen, Stephan A. Müller, Rosa Sinisalo, Mari Takalo, Petra Mäkinen, Teemu Kuulasmaa, Viivi Pekkala, Ana Galván del Rey, Sini-Pauliina Juopperi, Heli Jeskanen, Inka Kervinen, Kirsi Saastamoinen, Marja Niiranen, Sami V. Heikkinen, Mitja I. Kurki, Jarkko Marttila, Petri I. Mäkinen, Hannah Rostalski, Tomi Hietanen, Tiia Ngandu, Jenni Lehtisalo, Céline Bellenguez, Jean-Charles Lambert, Christian Haass, Juha Rinne, Juhana Hakumäki, Tuomas Rauramaa, Johanna Krüger, Hilkka Soininen, Annakaisa Haapasalo, Stefan F. Lichtenthaler, Ville Leinonen, Eino Solje, Mikko Hiltunen","doi":"10.1186/s13024-025-00830-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00830-3","url":null,"abstract":"Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer’s disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1–4 of TYROBP and causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelic TYROBP deletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelic TYROBP deletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelic TYROBP deletion carrier with NHD-type bone cysts. Mechanistically, monoallelic TYROBP deletion leads to decreased levels of DAP12 protein (encoded by TYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP. Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"8 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TDP-43 seeding activity in the olfactory mucosa of patients with amyotrophic lateral sclerosis","authors":"Maria Vizziello, Ilaria Linda Dellarole, Arianna Ciullini, Riccardo Pascuzzo, Annalisa Lombardo, Floriana Bellandi, Luigi Celauro, Claudia Battipaglia, Emilio Ciusani, Ambra Rizzo, Marcella Catania, Grazia Devigili, Sara Adriana Della Seta, Valentina Margiotta, Monica Consonni, Veronica Faltracco, Pietro Tiraboschi, Nilo Riva, Sara Maria Silvia Portaleone, Gianluigi Zanusso, Giuseppe Legname, Giuseppe Lauria, Eleonora Dalla Bella, Fabio Moda","doi":"10.1186/s13024-025-00833-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00833-0","url":null,"abstract":"In recent years, the seed amplification assay (SAA) has enabled the identification of pathological TDP-43 in the cerebrospinal fluid (CSF) and olfactory mucosa (OM) of patients with genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we investigated the seeding activity of TDP-43 in OM samples collected from patients with sporadic ALS. OM samples were collected from patients with (a) sporadic motor neuron diseases (MND), including spinal ALS (n = 35), bulbar ALS (n = 18), primary lateral sclerosis (n = 10), and facial onset sensory and motor neuronopathy (n = 2); (b) genetic MND, including carriers of C9orf72exp (n = 6), TARDBP (n = 4), SQSTM1 (n = 3), C9orf72exp + SQSTM1 (n = 1), OPTN (n = 1), GLE1 (n = 1), FUS (n = 1) and SOD1 (n = 4) mutations; (c) other neurodegenerative disorders (OND), including Alzheimer’s disease (n = 3), dementia with Lewy bodies (n = 8) and multiple system atrophy (n = 6); and (d) control subjects (n = 22). All samples were subjected to SAA analysis for TDP-43 (TDP-43_SAA). Plasmatic levels of TDP-43 and neurofilament-light chain (NfL) were also assessed in a selected number of patients. TDP-43_SAA was positive in 29/65 patients with sporadic MND, 9/21 patients with genetic MND, 6/17 OND patients and 3/22 controls. Surprisingly, one presymptomatic individual also tested positive. As expected, OM of genetic non-TDP-43-related MND tested negative. Interestingly, fluorescence values from non-MND samples that tested positive were consistently and significantly lower than those obtained with sporadic and genetic MND. Furthermore, among TDP-43-positive samples, the lag phase observed in MND patients was significantly longer than that in non-MND patients. Plasma TDP-43 levels were significantly higher in sporadic MND patients compared to controls and decreased as the disease progressed. Similarly, plasma NfL levels were higher in both sporadic and genetic MND patients and positively correlated with disease progression rate (ΔFS). No significant correlations were detected between TDP-43_SAA findings and the biological, clinical, or neuropsychological parameters considered. The OM of a subset of patients with sporadic MND can trigger seeding activity for TDP-43, as previously observed in genetic MND. Thus, TDP-43_SAA analysis of OM can improve the clinical characterization of ALS across different phenotypes and enhance our understanding of these diseases. Finally, plasma TDP-43 could serve as a potential biomarker for monitoring disease progression. However, further research is needed to confirm and expand these findings.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"14 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes","authors":"Sara Gutiérrez Fernández, Cristina Gan Oria, Dieter Petit, Wim Annaert, John M. Ringman, Nick C. Fox, Natalie S. Ryan, Lucía Chávez-Gutiérrez","doi":"10.1186/s13024-025-00832-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00832-1","url":null,"abstract":"Autosomal Dominant Alzheimer's Disease (ADAD), caused by mutations in Presenilins (PSEN1/2) and Amyloid Precursor Protein (APP) genes, typically manifests with early onset (< 65 years). Age at symptom onset (AAO) is relatively consistent among carriers of the same PSEN1 mutation, but more variable for PSEN2 and APP variants, with these mutations associated with later AAOs than PSEN1. Understanding this clinical variability is crucial for understanding disease mechanisms, developing predictive models and tailored interventions in ADAD, with potential implications for sporadic AD. We performed biochemical assessment of γ-secretase dysfunction on 28 PSEN2 and 19 APP mutations, including disease-associated, unclear and benign variants. This analysis has been valuable in the assessment of PSEN1 variant pathogenicity, disease onset and progression. Our analysis reveals linear correlations between the molecular composition of Aβ profiles and AAO for both PSEN2 (R2 = 0.52) and APP (R2 = 0.69) mutations. The integration of PSEN1, PSEN2 and APP correlation data shows parallel but shifted lines, suggesting a common pathogenic mechanism with gene-specific shifts in onset. We found overall “delays” in AAOs of 27 years for PSEN2 and 8 years for APP variants, compared to PSEN1. Notably, extremely inactivating PSEN1 variants delayed onset, suggesting that reduced contribution to brain APP processing underlies the later onset of PSEN2 variants. This study supports a unified model of ADAD pathogenesis wherein γ-secretase dysfunction and the resulting shifts in Aβ profiles are central to disease onset across all causal genes. While similar shifts in Aβ occur across causal genes, their impact on AAO varies in the function of their contribution to APP processing in the brain. This biochemical analysis establishes quantitative relationships that enable predictive AAO modelling with implications for clinical practice and genetic research. Our findings also support the development of therapeutic strategies modulating γ-secretase across different genetic ADAD forms and potentially more broadly in AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"9 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement","authors":"Natalie Grima, Andrew N. Smith, Claire E. Shepherd, Lyndal Henden, Thiri Zaw, Luke Carroll, Dominic B. Rowe, Matthew C. Kiernan, Ian P. Blair, Kelly L. Williams","doi":"10.1186/s13024-025-00820-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00820-5","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive muscle weakness and paralysis. While research has focused on understanding pathological mechanisms in the motor cortex and spinal cord, there is growing evidence that extra-motor brain regions may also play a role in the pathogenesis or progression of ALS. We generated 165 sample-matched post-mortem brain transcriptomes from 22 sporadic ALS patients with pTDP-43 pathological staging and 11 non-neurological controls. For each individual, five brain regions underwent mRNA sequencing: motor cortex (pTDP-43 inclusions always present), prefrontal cortex and hippocampus (pTDP-43 inclusions sometimes present), and occipital cortex and cerebellum (pTDP-43 inclusions rarely present). We examined gene expression, cell-type composition, transcript usage (% contribution of a transcript to total gene expression) and alternative splicing, comparing ALS-specific changes between brain regions. We also considered whether post-mortem pTDP-43 pathological stage classification defined ALS subgroups with distinct gene expression profiles. Significant gene expression changes were observed in ALS cases for all five brain regions, with the cerebellum demonstrating the largest number of total (> 3,000) and unique (60%) differentially expressed genes. Pathway enrichment and predicted activity were largely concordant across brain regions, suggesting that ALS-linked mechanisms, including inflammation, mitochondrial dysfunction and oxidative stress, are also dysregulated in non-motor brain regions. Switches in transcript usage were identified for a small set of genes including increased usage of a POLDIP3 transcript, associated with TDP-43 loss-of-function, in the cerebellum and a XBP1 transcript, indicative of unfolded protein response activity, in the motor cortex. Extensive variation in RNA splicing was identified in the ALS brain, with 26–41% of alternatively spliced genes unique to a given brain region. This included detection of TDP-43-associated cryptic splicing events such as the STMN2 cryptic exon which was shown to have a pTDP-43 pathology-specific expression pattern. Finally, ALS patients with stage 4 pTDP-43 pathology demonstrated distinct gene and protein expression changes in the cerebellum. Together our findings highlighted widespread transcriptome alterations in ALS post-mortem brain and showed that, despite the absence of pTDP-43 pathology in the cerebellum, extensive and pTDP-43 pathological stage-specific RNA changes are evident in this brain region.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"69 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities","authors":"Abdel Ali Belaidi, Ashley I. Bush, Scott Ayton","doi":"10.1186/s13024-025-00843-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00843-y","url":null,"abstract":"Apolipoprotein E (APOE- gene; apoE- protein) is the strongest genetic modulator of late-onset Alzheimer’s disease (AD), with its three major isoforms conferring risk for disease ε2 < ε3 < ε4. Emerging protective gene variants, such as APOE Christchurch and the COLBOS variant of REELIN, an alternative target of certain apoE receptors, offer novel insights into resilience against AD. In recent years, the role of apoE has been shown to extend beyond its primary function in lipid transport, influencing multiple biological processes, including amyloid-β (Aβ) aggregation, tau pathology, neuroinflammation, autophagy, cerebrovascular integrity and protection from lipid peroxidation and the resulting ferroptotic cell death. While the detrimental influence of apoE ε4 on these and other processes has been well described, the molecular mechanisms underpinning this disadvantage require further enunciation, particularly to realize therapeutic opportunities related to apoE. This review explores the multifaceted roles of apoE in AD pathogenesis, emphasizing recent discoveries and translational approaches to target apoE-mediated pathways. These findings underscore the potential for apoE-based therapeutic strategies to prevent or mitigate AD in genetically at-risk populations.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"17 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research models to study lewy body dementia","authors":"Suelen Lucio Boschen, Aarushi A. Mukerjee, Ayman H. Faroqi, Ben E. Rabichow, John Fryer","doi":"10.1186/s13024-025-00837-w","DOIUrl":"https://doi.org/10.1186/s13024-025-00837-w","url":null,"abstract":"Lewy body dementia (LBD) encompasses neurodegenerative dementias characterized by cognitive fluctuations, visual hallucinations, and parkinsonism. Clinical differentiation of LBD from Alzheimer’s disease (AD) remains complex due to symptom overlap, yet approximately 25% of dementia cases are diagnosed as LBD postmortem, primarily identified by the presence of α-synuclein aggregates, tau tangles, and amyloid plaques. These pathological features position LBD as a comorbid condition of both Parkinson’s disease (PD) and AD, with over 50% of LBD cases exhibiting co-pathologies. LBD’s mixed pathology complicates the development of comprehensive models that reflect the full spectrum of LBD’s etiological, clinical, and pathological features. While existing animal and cellular models have facilitated significant discoveries in PD and AD research, they lack specificity in capturing LBD’s unique pathogenic mechanisms, limiting the exploration of therapeutic avenues for LBD specifically. This review assesses widely used PD and AD models in terms of their relevance to LBD, particularly focusing on their ability to replicate human disease pathology and assess treatment efficacy. Furthermore, we discuss potential modifications to these models to advance the understanding of LBD mechanisms and propose innovative research directions aimed at developing models with enhanced etiological, face, predictive, and construct validity.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"70 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model","authors":"Shuo Wang, Chuangye Qi, Chetan Rajpurohit, Baijayanti Ghosh, Wen Xiong, Baiping Wang, Yanyan Qi, Sung Hee Hwang, Bruce D. Hammock, Hongjie Li, Li Gan, Hui Zheng","doi":"10.1186/s13024-025-00844-x","DOIUrl":"https://doi.org/10.1186/s13024-025-00844-x","url":null,"abstract":"The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer’s disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood. Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice. This was followed by single-nucleus RNA-sequencing (snRNA-seq), biochemical and immunohistochemical analysis, and behavioral assessments. Additionally, we examined the effects of the sEH-EET pathway in primary microglia cultures and human induced pluripotent stem cell (iPSC)-derived neurons exhibiting seeding-induced Tau inclusions. sEH inhibition improved cognitive function, rescued neuronal cell loss, and reduced Tau pathology and microglial reactivity. snRNA-seq revealed that TPPU treatment upregulated genes involved in actin cytoskeleton and excitatory synaptic pathways. Treatment of human iPSC-derived neurons with TPPU enhanced synaptic density without affecting Tau accumulation, suggesting a cell-autonomous neuroprotective effect of sEH blockade. Furthermore, sEH inhibition reversed disease-associated and interferon-responsive microglial states in PS19 mice, while EET supplementation promoted Tau phagocytosis and clearance in primary microglia cultures. These findings demonstrate that sEH blockade or EET augmentation confers therapeutic benefit in neurodegenerative tauopathies by simultaneously targeting neuronal and microglial pathways.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health","authors":"Jolien Perneel, Miranda Lastra Osua, Sara Alidadiani, Nele Peeters, Linus De Witte, Bavo Heeman, Simona Manzella, Riet De Rycke, Mieu Brooks, Ralph B. Perkerson, Elke Calus, Wouter De Coster, Manuela Neumann, Ian R. A. Mackenzie, Debby Van Dam, Bob Asselbergh, Tommas Ellender, Xiaolai Zhou, Rosa Rademakers","doi":"10.1186/s13024-025-00831-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00831-2","url":null,"abstract":"Genetic variation in Transmembrane protein 106B (TMEM106B) is known to influence the risk and presentation in several neurodegenerative diseases and modifies healthy aging. While evidence from human studies suggests that the risk allele is associated with higher levels of TMEM106B, the contribution of elevated levels of TMEM106B to neurodegeneration and aging has not been assessed and it remains unclear how TMEM106B modulates disease risk. To study the effect of increased TMEM106B levels, we generated Cre-inducible transgenic mice expressing human wild-type TMEM106B. We evaluated lysosomal and neuronal health using in vitro and in vivo assays including transmission electron microscopy, immunostainings, behavioral testing, electrophysiology, and bulk RNA sequencing. We created the first transgenic mouse model that successfully overexpresses TMEM106B, with a 4- to 8-fold increase in TMEM106B protein levels in heterozygous (hTMEM106B(+)) and homozygous (hTMEM106B(++)) animals, respectively. We showed that the increase in TMEM106B protein levels induced lysosomal dysfunction and age-related downregulation of genes associated with neuronal plasticity, learning, and memory. Increased TMEM106B levels led to altered synaptic signaling in 12-month-old animals which further exhibited an anxiety-like phenotype. Finally, we observed mild neuronal loss in the hippocampus of 21-month-old animals. Characterization of the first transgenic mouse model that overexpresses TMEM106B suggests that higher levels of TMEM106B negatively impacts brain health by modifying brain aging and impairing the resilience of the brain to the pathomechanisms of neurodegenerative disorders. This novel model will be a valuable tool to study the involvement and contribution of increased TMEM106B levels to aging and will be essential to study the many age-related diseases in which TMEM106B was genetically shown to be a disease- and risk-modifier. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic effects of adipose-derived mesenchymal stem cells combined with glymphatic system activation in prion disease","authors":"Mohammed Zayed, Yong-Chan Kim, Byung-Hoon Jeong","doi":"10.1186/s13024-025-00835-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00835-y","url":null,"abstract":"There is currently no effective therapy for prion diseases. The glymphatic system is an organized system of perivascular spaces that facilitates the removal of metabolic waste from the brain. This study demonstrates the therapeutic potential of a combination therapy of adipose-derived mesenchymal stem cells (AdMSCs) and a glymphatic system-activated drug, clonidine, against prion disease. The therapy has the potential to clear PrPSc accumulation, ameliorate astrocytosis, and prolong the survival time of ME7-infected mice.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"42 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM2 and sTREM2 in Alzheimer’s disease: from mechanisms to therapies","authors":"Lianshuai Zhang, Xianyuan Xiang, Yahui Li, Guojun Bu, Xiao-Fen Chen","doi":"10.1186/s13024-025-00834-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00834-z","url":null,"abstract":"Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor predominantly expressed by microglia in the brain. Recent studies have established TREM2 as a central immune signaling hub in neurodegeneration, where it triggers immune responses upon sensing pathological development and tissue damages. TREM2 binds diverse ligands and activates downstream pathways that regulate microglial phagocytosis, inflammatory responses, and metabolic reprogramming. Interestingly, TREM2 exists both in its membrane-bound form and as a soluble variant (sTREM2), that latter is generated through proteolytic shedding or alternative splicing and can be detected in cerebrospinal fluid and plasma. Emerging clinical and preclinical evidence underscores the potential of TREM2 and sTREM2 as diagnostic biomarkers and therapeutic targets in Alzheimer’s disease (AD). This review provides a comprehensive overview of the molecular functions, regulatory mechanisms, and pathological implications of TREM2 and sTREM2 in AD. Furthermore, we explore their potential roles in diagnostics and therapeutics while suggesting key research directions for advancing TREM2/sTREM2-based strategies in combating AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"39 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}